The Medical RevolutionWhere are the cures promised by stem cells, gene therapy, and the human genome?

Dr. J. William Langston has been researching Parkinson’s disease for 25 years. At one time, it seemed likely he’d have to find another disease to study, because a cure for Parkinson’s looked imminent. In the late 1980s, the field of regenerative medicine seemed poised to make it possible for doctors to put healthy tissue in a damaged brain, reversing the destruction caused by the disease.

Langston was one of many optimists. In 1999, the then-head of the National Institute of Neurological Disorders and Stroke, Dr. Gerald Fischbach, testified before the Senate that with “skill and luck,” Parkinson’s could be cured in five to 10 years. Now Langston, who is 67, doesn’t think he’ll see a Parkinson’s cure in his professional lifetime. He no longer uses “the C word” and acknowledges he and others were naive. He understands the anger of patients who, he says, “are getting quite bitter” that they remain ill, long past the time when they thought they would have been restored to health.

The disappointments are so acute in part because the promises have been so big. Over the past two decades, we’ve been told that a new age of molecular medicine—using gene therapy, stem cells, and the knowledge gleaned from unlocking the human genome—would bring us medical miracles. Just as antibiotics conquered infectious diseases and vaccines eliminated the scourges of polio and smallpox, the ability to manipulate our cells and genes is supposed to vanquish everything from terrible inherited disorders, such as Huntington’s and cystic fibrosis, to widespread conditions like cancer, diabetes, and heart disease.

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Adding to the frustration is an endless stream of laboratory animals that are always getting healed. Mice with Parkinson’s have been successfully treated with stem cells, as have mice with sickle cell anemia. Dogs with hemophilia and muscular dystrophy have been made disease-free. But humans keep experiencing suffering and death. Why? What explains the tremendous mismatch between expectation and reality? Are the cures really coming, just more slowly than expected? Or have scientists fundamentally misled us, and themselves, about the potential of new medical technologies?

The Brain Is Not a Pincushion
Parkinson’s disease was long held out as the model for new knowledge and technologies eradicating illnesses. Instead, it has become the model for its unforeseen consequences.

Langston, head of the Parkinson’s Institute and Clinical Center, explains that scientists believed the damage to patients took place in a discrete part of the brain, the substantia nigra. “It was a small target. All we’d have to do was replace the missing cells, do it once, and that would cure the disease,” Langston says. “We were wrong about that. This disease hits many other areas of the brain. You can’t just put transplants here and there. The brain is not a pincushion.”

Parkinson’s patients in the 1980s were guinea pigs, getting fetal tissue transplants—a precursor of stem-cell therapy—in their brains. After reports of dramatic improvement, it seemed like a new era had begun. But to make sure the results were real, in the 1990s a group of patients agreed to undergo a double-blind study: Half would get brain surgery with the fetal tissue, half would get holes drilled in their heads and no transplant. (Yes, there are patients willing to have useless holes drilled in their heads for the sake of advancing science.)

It was a huge disappointment when the two groups showed only a marginal difference in disease manifestation—the previous benefits, it turned out, were largely placebo effect. Then, horrifyingly, a year after the surgery, a major difference appeared. Fifteen percent of the patients who received the fetal tissue developed “tragic, catastrophic” uncontrollable movements.

Of course, one experiment gone wrong—even dreadfully wrong—shouldn’t and hasn’t shut down an entire field of inquiry. The long road of medical advances is always littered with bodies. But questions loom over inserting new tissue or genes into patients: Will the fix take, and will the new material sustain its function over the course of a patient’s life? Now that some of those original Parkinson’s fetal-tissue recipients are dying, autopsies reveal the encouraging finding that the fetal tissue remained viable. But there’s also bad news. The unpleasant surprise, which Langston says “no one saw coming,” is that over the years, the healthy, transplanted cells developed characteristic evidence of Parkinson’s. This meant that instead of the new cells taking over for damaged ones, they too succumbed to the not-yet-understood disease process.

Langston says replacing tissue in the brain damaged by neurodegenerative disease, such as Alzheimer’s or amyotrophic lateral sclerosis—Lou Gehrig’s disease—is currently beyond our capacity. “If there’s a broad message, it’s that human neurodegenerative disease is tough. We’ve never cured one, we’ve never even proven to slow one down.”

The Problems With MiraclesAstounding technological breakthroughs bring the promise of extraordinary cures. An enthusiastic advocate for this position—and no wonder, since he’s been instrumental in bringing many of these advances—is Dr. Francis Collins. Collins, now the director of the National Institutes of Health, was the head of the Human Genome Project, the massive, international undertaking that after more than a decade sequenced the 3 billion base pairs of our DNA. His new book The Language of Life: DNA and the Revolution in Personalized Medicine is a manifesto of biotech optimism. Even so, his distinguished career demonstrates how great the gap is between discovery and cure.

Collins was on the team of scientists that identified the gene for cystic fibrosis more than 20 years ago, after what he describes as “many long years of torturous work.” With that discovery came the belief that it could be beaten. “Cystic fibrosis seemed like the perfect target for gene therapy,” Collins said in an interview. The idea behind gene therapy is that bad genes can be replaced by good ones, like swapping out defective tires. The cystic fibrosis fix was elegantly simple: Deliver normal genes into the lung, and they would function in place of the faulty ones. Thrillingly, Collins’ team got this to work in a laboratory culture within a year of the identification of the CF gene.

But human lungs have not been so cooperative: Numerous attempts over the decades have failed. “Everyone underestimated how hard it would be in the first couple of years,” Collins told me.

Gene therapy remains experimental 20 years after its first human trials because of a series of vexing problems. For one thing, the new gene has to get to the right place and continue working—without causing any unwanted side effects. In 1999, 18-year-old Jesse Gelsinger became a pivotal figure in gene therapy, an unintended martyr. Gelsinger suffered from a genetic liver disorder, though he had a mild case that could be treated with drugs. He volunteered for experimental gene therapy to correct it. A few hours after receiving a transfusion of normal genes delivered inside a cold virus, he became feverish; within days, he was dead of massive organ failure. His death set back the entire field and ended the hope that curing disease by manipulating genes would be simple and safe.

But scientists kept at it. In some ways, gene therapy for boys with a deadly immune disorder, X-linked severe combined immune deficiency, also known as “bubble boy” disease, is the miracle made manifest. Inserting good genes into these children has allowed some to live normal lives. Unfortunately, within a few years of treatment, a significant minority have developed leukemia. The gene therapy, it turns out, activated existing cancer-causing genes in these children. This results in what the co-discoverer of the structure of DNA, James Watson, calls “the depressing calculus” of curing an invariably fatal disease—and hoping it doesn’t cause a sometimes-fatal one.

Then there are stem cells, which tantalize with their myriad possibilities: allowing diabetics to throw away their insulin, growing healthy cardiac tissue after a heart attack, restoring function to people with spinal cord injury (for which the Food and Drug Administration just approved the first embryonic stem cell trial). Embryonic stem cells—the subject of so much controversy—were first cultured in the lab a little more than a decade ago; in 2006, there was another breakthrough when adult cells were coaxed into becoming induced pluripotent stem cells. (Bone marrow transplants use adult stem cells, a treatment that has been used for decades.) But getting stem cells to work in the human body is neither an easy nor necessarily benign process. Researchers are concerned that stem cells, once let loose, might take a wrong turn; heart cells, for instance, could end up in the brain. They could also proliferate excessively, causing damage to nearby tissues. They could generate tumors. These aren’t just hypotheticals. Doctors in Moscow injected neural embryonic stem cells into the brain and spinal fluid of a boy suffering from a rare, disabling, inherited disease, ataxia telangiectasia. The good news is that the transplanted cells persisted. The bad news is that they weren’t effective in treating his disease. The worse news is the transplanted cells caused tumors in the boy’s brain and spine.

The researchers who analyzed the boy’s case acknowledge that any bold, new therapy for devastating diseases often carries grave risks. As Francis Collins says, “I’m very excited for the potential of stem cells” but adds, “We have to be very careful.” He’s careful enough not to venture a timetable as to when their potential will reach patients.

Why Is It So Hard?
When Dr. Nancy Wexler was a young woman, she decided she would never have children. Her mother had been diagnosed with Huntington’s disease, the rare, inherited disorder that slowly destroys people’s brains, cripples their bodies, eventually killing them. A child of someone with Huntington’s has a 50-50 chance of developing, and succumbing to, the disease.

Back before the technology existed to easily sequence DNA, Wexler, who has devoted her life to conquering Huntington’s, was determined to identify the gene that destroyed her mother. Some scientists told her it was a task so futile that it could take 100 years. But in 1993, after 15 years of effort, a team identified the mutated gene. Scientists went on to discover the protein produced by the mutated gene that causes the damage to the brain. With this crucial knowledge, researchers hoped they could one day disable the mutated gene before it disabled its victims.

But even now, a Huntington’s diagnosis means the agonizing loss of one’s faculties and eventual death. As Wexler says, “The struggle is, Why is this so hard? To this day, we still don’t know what the protein does.”

The New York Times recently pointed out that 10 years after the first draft of the human genome was announced, the hoped-for ability to identify the genetic causes of our major killers such as cancer and heart disease has been mostly a bust. Dozens, even hundreds, of potential gene variations have been linked to the diseases. As such mutations frequently fail to predict who falls ill, scientists wonder whether some once-promising gene associations could be simply coincidences. Yet even knowing exactly which mutated gene causes a disease—as in Huntington’s and cystic fibrosis—doesn’t necessarily mean it is either preventable or curable.

Sometimes our expanding knowledge does reveal new avenues for therapeutic interventions, as it also taunts with its complexity. Dr. Bruce Stillman, director of the Cold Spring Harbor Laboratory, says medical progress would be a stuck without the advancements made in molecular biology over the past 40 years. He cites the successes of Herceptin for breast cancer and Gleevec for chronic myeloid leukemia, two drugs made possible by our growing understanding of how cells work. We’ve also learned, he says, that cancer is not one disease but many subtypes, so there will never be a single penicillin-like cure. “If anything, cancer has become a bigger problem because of the nature of our understanding,” Stillman says.

Do You Really Want To Know?
The day is approaching when getting one’s genome sequenced will cost only a few thousand dollars. Already, Glenn Close, Henry Louis Gates Jr., and a poodle named Shadow have had theirs done. Collins says this will be a crucial part of everyone’s medical record, allowing us to see what dangers lurk in our genes. But Dr. David Goldstein, director of Duke University’s Center for Human Genome Variation, says, “Right now we know very, very little of the genetics of the diseases that most people will get.”

Science blogger Daniel MacArthur has written that although we can peer into our DNA, that doesn’t mean we can make much sense of it: “[E]ach of us have genomes littered with genetic variants that look like nasty mutations but have little or no effect on health. … [S]equencing technology is still moving far faster than our ability to interpret the resulting data.”

The state of our ignorance is illustrated by the recent sequencing of the genome of Bishop Desmond Tutu and four Bushmen. Three of the Bushmen had a gene mutation associated with a liver disease that kills people while young. But the Bushmen are all over 80—which means either the variation doesn’t actually cause the disease, or there are other factors protecting the Bushmen.

Parkinson’s expert William Langston says that when the human genome was sequenced a decade ago, “people thought all key diseases were fundamentally genetic. Once we got the genes, it would all fall into place.” But in the years since, there has been a growing realization that environmental influences can be just as important. While our genome is finite, environmental influences on our gene expression—the food we eat, the infections we contract, the stress we’re under—are infinite.

We know we can acquire genetic damage through our behavior—ask a smoker with lung cancer. But there is a developing school of research, the study of epigenomics, that seeks to help explain how the interaction of our genes and environment causes disease. Epigenomics studies the chemical tags that lie just outside our genes and direct whether particular genes switch on or off. One thing that distinguished our epigenome from our genome is its flexibility, the way it changes in response to environmental forces. For example, a mother rat that grooms her pups sets off epigenetic changes that result in her pups growing up to be calm adults. Neglected pups grow up anxious and have more diabetes and heart disease—the stress of neglect causes changes to the chemical tags of the epigenome, which then results in the silencing or expression of certain genes. Amazingly, some of these nongenetic changes can be passed to the next generation: Unlicked pups grow up to be unlicking mothers, who beget more unlicked pups.

So the long, expensive process of mapping the epigenome hasbegun, a massive undertaking that, the NIH notes with supreme understatement, will “require the development of better technologies.”

A recent study illustrates that sometimes even our most sophisticated tools only get us deeper into the mystery of our biology. Researchers at the University of California-San Francisco’s Multiple Sclerosis Research Group conducted one of the most comprehensive examinations to date of the genome, and even part of the epigenome, of a set of identical twins, only one of whom had been stricken with MS. Scientists are sure MS is caused by some combination of genetic susceptibility and external trigger. Finding the differences between the twins, it was hoped, could help identify why one fell ill. But the disease hunters failed to turn up any illuminating disparities.

The Sales Pitch
If you follow the news, you might have recently gotten the impression that breast cancer is about to be eliminated by a simple vaccination. That’s what the lead researcher of a study of a breast cancer vaccine in mice would like you to think. “We believe that this vaccine will someday be used to prevent breast cancer in adult women in the same way that vaccines prevent polio and measles in children,” said Dr. Vincent Tuohy in a press release from the Cleveland Clinic.

Then there was the experiment that cured mice of the eye disease retinitis pigmentosa using nanotechnology. The editor of the journal that published the study, Dr. Gerald Weissmann, said, “As we have expanded our understanding of evolution, genetics, and nanotechnology, chances are that ‘miraculous’ cures will become as commonplace as those claimed by faith-healers past and present.”

This is the kind of talk that makes the public wonder why their own doctors aren’t dispensing miracles. There are forces, both external and internal, on scientists that almost require them to oversell. Without money, there’s no science. Researchers must constantly convince administrators who control tax dollars, investors, and individual donors that the work they are doing will make a difference. Nancy Wexler says that in order to get funding, “You have to promise cures, that you’ll meet certain milestones within a certain time frame.”

The infomercial-level hype for both gene therapy and stem cells is not just because scientists are trying to convince funders, but because they want to believe. Dr. Theodore Friedmann, professor of pediatrics at the University of California-San Diego Medical Center and the former president of the American Society of Gene and Cell Therapy, was a gene therapy pioneer. He says the nature of science is that what seem like sudden breakthroughs are usually preceded by years of persistent failure and incremental victory. For example, successful organ transplantation took decades to achieve. Before doctors came up with a drug regime to get around the deadly problem of organ rejection, surgeons tried such unsuccessful interventions as destroying patients’ immune systems through massive doses of radiation and even transplanting a kidney encased in a plastic bag.

But he acknowledges his profession forgot these lessons when gene therapy first appeared: “Well-meaning scientists got carried away by their own enthusiasm and expressed this to patients desperately looking for help.”

The cure for this—for both scientists and the public—is simple but not very appealing: humility and patience. Friedmann says discouragement or disappointment in the pace of gene therapy, for example, is misplaced. “It hasn’t been a long time. In comparison to the ways in which advances in medicine come, it’s been a short time,” he says. He says interfering with fundamental biological processes inevitably causes unforeseen difficulties.

Still OptimisticSo, that’s it? The medicine of the future is always going to be out of reach? Some people say it’s slowly arriving. There are researchers who stuck with gene therapy and are starting to see results. For instance, a rare type of inherited blindness has been successfully treated in a small study. The eye may be a particularly receptive place for gene therapy because it is a relatively contained space that does not mount a large immune response. Dismissing such caveats, Theodore Friedmann says restoring vision to blind patients is quite enough proof that gene therapy works. “If that’s not a new era in medicine, I don’t know what is!”

Even William Langston says he is feeling renewed optimism about the prospects for Parkinson’s. Maybe there won’t be a cure, or even a reversal once major damage is done, but the possibility remains that if the disease could be identified much earlier, when its effects are still minor, drugs now in the testing phase might be able to halt the disease’s progression. Those are big “ifs” and “mights,” but Langston says one study, called ADAGIO, has shown promise with newly diagnosed patients.

He also thinks that stem cells have the potential to illuminate the still-unknown disease process of Parkinson’s. If cells from Parkinson’s patients can be returned to their undifferentiated state, coaxed in the laboratory to become dopamine cells that then develop characteristics of the disease, he says, “we will have Parkinson’s in a dish.” That would be a technological breakthrough both for understanding how the disease starts and for testing potential therapeutics without endangering patients.

If scientists weren’t optimists, science would be almost impossible to do. Medical research is too frustrating, demanding, and grueling to think that all the years of devotion won’t pay off. As Nancy Wexler says, “If I didn’t feel what our foundation is doing was going to make a difference, it would just be too unbearable. But you still have the question, Am I doing the right thing?”